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Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation

Author

Listed:
  • Nick Huang

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Thomas Winans

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Brandon Wyman

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Zachary Oaks

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Tamas Faludi

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Gourav Choudhary

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Zhi-Wei Lai

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Joshua Lewis

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Miguel Beckford

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Manuel Duarte

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Daniel Krakko

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Akshay Patel

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Joy Park

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Tiffany Caza

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Mahsa Sadeghzadeh

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Laurence Morel

    (University of Florida)

  • Mark Haas

    (Cedars-Sinai Medical Center)

  • Frank Middleton

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Katalin Banki

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

  • Andras Perl

    (State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse
    State University of New York, Upstate Medical University, Norton College of Medicine, Syracuse)

Abstract

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4−CD8− double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.

Suggested Citation

  • Nick Huang & Thomas Winans & Brandon Wyman & Zachary Oaks & Tamas Faludi & Gourav Choudhary & Zhi-Wei Lai & Joshua Lewis & Miguel Beckford & Manuel Duarte & Daniel Krakko & Akshay Patel & Joy Park & T, 2024. "Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46441-2
    DOI: 10.1038/s41467-024-46441-2
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    References listed on IDEAS

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    1. Victoria Ozberk & Mehfuz Zaman & Ailin Lepletier & Sharareh Eskandari & Jacqualine Kaden & Jamie-Lee Mills & Ainslie Calcutt & Jessica Dooley & Yongbao Huo & Emma L. Langshaw & Glen C. Ulett & Michael, 2023. "A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ruth Milkereit & Avinash Persaud & Liviu Vanoaica & Adriano Guetg & Francois Verrey & Daniela Rotin, 2015. "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    3. Anders A Bengtsson & Johan Trygg & Dirk M Wuttge & Gunnar Sturfelt & Elke Theander & Magdalena Donten & Thomas Moritz & Carl-Johan Sennbro & Frida Torell & Christian Lood & Izabella Surowiec & Stefan , 2016. "Metabolic Profiling of Systemic Lupus Erythematosus and Comparison with Primary Sjögren’s Syndrome and Systemic Sclerosis," PLOS ONE, Public Library of Science, vol. 11(7), pages 1-15, July.
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